# Factors associated with protection from MASLD in type 2 diabetes: A prospective study integrating longitudinal MRI/MRE and stable isotope tracing

## TL;DR

This study finds that lower BMI, insulin resistance, and triglycerides may protect some type 2 diabetes patients from developing liver disease.

## Contribution

The study identifies novel protective factors against MASLD in type 2 diabetes using longitudinal MRI and isotope tracing.

## Key findings

- Lower BMI, HOMA-IR, and triglycerides were strongest predictors of protection from MASLD.
- Reduced hepatic de novo lipogenesis was observed in individuals free from MASLD.
- Managing modifiable risk factors may help prevent MASLD in type 2 diabetes patients.

## Abstract

Type 2 diabetes is one of the strongest risk factors for the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, we aimed to identify factors associated with protection from MASLD in a prospective cohort of individuals with type 2 diabetes.

This prospective study included 148 individuals with type 2 diabetes who underwent advanced liver phenotyping using MRI and MRE techniques at baseline and 2-year follow-up. Protection from MASLD was defined as the absence of hepatic steatosis (MRI-proton density fat fraction <5%) and significant fibrosis (MRE <3 kPa) at both time points. Factors associated with protection from MASLD were assessed using Firth’s penalized logistic regression. Regularized logistic regression models were fitted as complementary analyses.

The mean (SD) age and BMI were 65 (8) years and 30.4 (4.3) kg/m2, respectively. After a median follow-up of 2 (1.5–2.4) years, 27 (18%) individuals demonstrated an absence of MASLD. Across all modeling approaches, lower BMI (odds ratio [OR] 0.81, 95% CI 0.64–0.98; p = 0.029), lower HOMA-IR (OR 0.59, 95% CI 0.39–0.83; p = 8.6e-4), and lower circulating triglycerides (OR 0.986, 95% CI 0.973–0.997; p = 0.011) emerged as the strongest predictors of protection from MASLD. An exploratory analysis of 11 individuals with type 2 diabetes from an independent cohort, with hepatic de novo lipogenesis quantified by stable isotope tracing, revealed lower hepatic de novo lipogenesis in those free from MASLD.

Managing modifiable risk factors, such as body weight and lipid profile, may be critical for preventing MASLD development in individuals with type 2 diabetes.

Understanding factors conferring protection from metabolic dysfunction-associated steatotic liver disease (MASLD) in individuals with type 2 diabetes represents a novel research avenue which has not been systematically explored. In this prospective cohort of 148 individuals with type 2 diabetes undergoing advanced liver phenotyping at baseline and 2-year follow-up, we identified lower BMI, lower HOMA-IR, and lower circulating triglycerides as the strongest predictors of remaining free of MASLD. Additionally, by performing an exploratory analysis in an independent cohort of 11 individuals with type 2 diabetes with tracer data, we found that lower hepatic de novo lipogenesis may underlie this protective phenotype. These findings suggest that managing modifiable risk factors, such as body weight and lipid profile, may be critical for preventing MASLD development and progression in individuals with type 2 diabetes.

Image 1

•Some individuals with type 2 diabetes appear protected from MASLD, but the factors driving this protection remain unclear.•In a 2-year prospective type 2 diabetes cohort, lower BMI, lower HOMA-IR, and lower triglycerides predicted MRI-defined protection from MASLD.•Reduced hepatic de novo lipogenesis may underlie this protected phenotype.•These findings could guide strategies to lower MASLD risk and progression in patients with type 2 diabetes.

Some individuals with type 2 diabetes appear protected from MASLD, but the factors driving this protection remain unclear.

In a 2-year prospective type 2 diabetes cohort, lower BMI, lower HOMA-IR, and lower triglycerides predicted MRI-defined protection from MASLD.

Reduced hepatic de novo lipogenesis may underlie this protected phenotype.

These findings could guide strategies to lower MASLD risk and progression in patients with type 2 diabetes.